Anti-anaphylactic compositions



United States Patent 3,167,475 ANTl-ANAPHYLACTEC QOMPUSITEUNS SiegfriedGottfried, llford, and Lily Banendale, London,

England, assignors to lfiiorex Laboratories Limited, London, England, acorporation of the United Kingdom No Drawing. Filed Bee. 19, 1960, Ser.No. 76,504 Claims priority, application Great Britain, Dec. 31, 1959,44,460/59 2 Claims. (Cl. 167-65) The present invention is concerned withnew antianaphylactic compositions.

Using the test procedure outlined by Herxheimer, J. Physiol., 117, 251(1952), we have found that the lower alkanolamines and compounds derivedtherefrom possess valuable anti-anaphylactic activity when administeredexperimentally to guinea pigs. These alkanolamine compounds can beadministered in simple vehicles, such as distilled water, or in moreelaborate vehicles, such as tablet bases. These alkanolamine compoundsproduce a protective action which can be observed as an increase in thetime in which sensitized animals can tolerate an antigen withoutundergoing anaphylactic shock.

We have found that the protective action obtained by the use of thesealkanolamine compounds is not very great when they are administered ontheir own but when administered in conjunction with knownanti-histaminics which themselves only have a slight protective action,a considerable potentiation of activity is obtained. We have also foundthat a potentiation of the activity of these alkanolamine compounds isachieved when they are combined with expectorants, anti-tussives,anti-histaminics, anti-asthmatics, bronchodilators, corticosteroids,anti-biotics, bactericidals, tbacteriostatics and/or anti-inflammatoryagents.

This discovery has obvious valuable clinical applications since thecompositions should be of considerable value in the treatment ofallergic conditions, such as asthma, urticaria or conditions in whichsome allergic mechanism represents a contributory factor.

The low molecular weight alkanolamines which are used according to thepresent invention may be represented by the general formula:

N-OHCH2O1I R3 R1 wherein R R and R which may be same or different, arehydrogen atoms or methyl or ethyl radicals; and the esters, salts,amides and quaternary ammonium salts thereof.

Examples of compounds which may be added to the alkanolamines areipecacuanha and cocillana (i.e., expectorants), codeine and pholcodine(i.e., anti-tussives), mepyramine maleate and phenindamine tartrate(i.e., anti-histiminics), adrenaline and ephedrine (i.e.,antiasthmatics), prednisone and triamcinolone (i.e., corticosteroids andcorticosteroid-like compounds), tetracycline and chloramphenicol (i.e.,antibiotics), creosote and cetrimide B.P. (i.e., bactericides), domiphenbromide and benzalkonium chloride (i.e., bacteriostatics), aspirin,cortisone), xanthoglabrol, glycyrrhetinic acid and derivatives thereof(i.e., anti-inflammatory agents), and xanthines and ephedrine (i.e.,bronchodilators). Mepyramine is 2-[ (Z-dimethylamino-ethyl)(p-methoxybenzyl) amino]-pyridine; domiphen isdodecyldim=ethyl-(2-phenoxy-ethyl)ammonium bromide; and cetrimide iscetyltrimethylammonium bromide. The compositions according to thepresent invention, which have been shown to exhibit true synergism, maybe made up in the form of inhalations, aerosols, tablets, injections,onematas, suppositories, ointments, lotions and suspensions by admixiceture with an appropriate solid or liquid pharmaceutical carrier ordiluent.

Examples of alkanolamines coming within the scope of the above generalformula are ethanolamine, N-methylethanolamine,'N,N-dimethyl-ethanolamine, choline, N- ethyl-ethanolamine,N,N-diethyl-ethanolamine, N,N,N- triethyl-N-ethylol ammonium salts,N-methyl-Z-aminopropanol, N,N-dimethyl-2-amino-propanol,2-aminopropanol, N,N,N-trimethyl-N-(Z-propylol) ammonium salts,phoshatidyl-ethanolamine and ethanolamine phosphatase.

It is thought that the mechanism of the synergism of the alkanolaminesof the above general formula and, for example, anti-histamines, can beoutlined as follows: in 1956 Brocklehurst described at the Cibafoundation symposium on histamine, the liberation from sensitized guineapig lung of two active principles which can be described as chemicalmediators of anaphylaxis. He described these chemical mediators ashistamine and the slow reacting substances of anaphylaxis (SRS/A). Wehave shown experimentally that alkanolamines and derivatives thereof ofthe above given general formula are capable of preventing the release ofSRS/A in anaphylaxis. They have a negligible effect on the release ofhistamine in the same condition and it is, therefore, concluded that thehistamine which is released in anaphylaxis is eifectively controlled bythe anti-histamine contained in the composition and that thealkanolamine derivatives potentiate this action by preventing therelease of SRS/A, which is, for example, normally responsible forbronchospasm, even in the presence of anti-histamine molecules which areincapable of antagonising the pharmacological action of SRS/A.

We have also found that synergism exists between the alkanolaminesaccording to the present invention and blood pressure-reducing drugs,such as pentaerythrityl tetranitrate, diuretic drugs, such asacetazolarnide and chloroth'iazide, and anti-coagulant drugs, such asphenindione. Such compositions may be used, for example, in thetreatment of arteriosclerosis and coronary thromboses.

The following examples are given for the purpose of illustrating thepresent invention.

(1) Inhalation:

500 mg. antazolidine sulphate 1000 mg. ethanolamine hydrochloride 900mg. sodium chloride 9000 mg. friars balsam ml. water 1 tablespoonful isadded to about /2 pint hot water and the vapours given oil are inhaled.Tablet: 25 mg, mepyramine maleate 5 mg. choline hydrochloride incipient,q.s.

Fiat tabella. Injection: 200 mg. diphenylhydramine hydrochloride 1000mg. ethyanolamine succinate 900 mg. sodium chloride 100 ml. distilledwater 900 mg. domiphen bromide The resultant solution is sterilized byheating for 30 minutes at C. 1 cc. of the sterilized solution isinjected as required, Enema: 200 mg. ethanolamine maleate '100 mg.mepyramine maleate mg. sodium chloride 10 mg. prednisolone phosphate ml.distilled water 0.1% w./w. cetrimide (5) Suppository:

3 g. chloramphenicol 6 g. choline hydrochloride 3 Q.s. cocoa butterFiatto mould -30 suppositories. Ointment: 2 g. .benzalkonium chloride 1g. glycyrrhetinic acid 5 g. ethanolamine hydrochloride Ad 100 g.water-miscib1e ointment base Lotion: 200mg. glycyrrhetinic acidhemisuccinate, disodium salt 1000 mg. ethanolami'ne maleate 900 mg.sodium chloride 900 mg. domiphen bromide 100 ml. distilled Water What weclaim is:

1. A tablet consisting essentially of 1 part by weight of 2 [-(2dimethylamino ethyl) (p methoxybenzyl) amino1-pyridine maleate and 2parts by Weight of choline hydrochloride.

2. Anti-anaphylactic composition of matter consisting essentially of 2-5parts by Weight of a member selected from the group consisting ofalkanolamines of the formula and the pharmaceutically acceptablequaternary ammonium salts and pharmaceutically acceptable bases thereof,in which R; is a member selected from the group consisting of hydrogen,methyl and ethyl, R is a member selected from the group consisting ofhydrogen, methyl and ethyl, and R is a member selected from the groupconsisting of hydrogen, methyl and ethyl and one part by Weight of2-[(2-dimethy1aminoethyl) (p-methoxybenzyl)-amino]-pyridine maleate, inadmixture with a pharmaceutical carrier.

References Cited by the Examiner Remington, Practice of Pharmacy, 1956,page 1011.

Merck Index, 7th Ed, 1960, pages 84, 253, 390, 794, 84-8, 1056.

J. of Am. Med. Assoc., February 28, 1959, 169:9, 124/ 956.

Swineford, J. of Allergy, 27:2, pp. 137-142, March 1956.

Kile: Antibiotic Medicine and Clinical Therapy, vol. 9 No. 4, September1958, pp. 578-581.

American Drug Index, 1959, pp. 514518, p. 160.

LEWIS GOTTS, Primary Examiner.

W. B. KNIGHT, FRANK CACCIAPAGLIA, 111.,

Examiners.

2. ANTI-ANAPHYLACTIC COMPOSITION OF MATTER CONSISTING ESSENTIALLY OF 2-5PARTS BY WEIGHT OF A MEMBER SELECTED FROM THE GROUP CONSISTING OFALKANOLAMINES OF THE FORMULA